chicago-kent journal of intellectual property

Chicago-Kent Journal of Intellectual Property Chicago-Kent Journal of Intellectual Property

Volume 18 Issue 3 Article 6

6-4-2019

Assessment of Disclosure In European Prodrug Patent Claims Assessment of Disclosure In European Prodrug Patent Claims

Mari Minn PhD, LLM

Follow this and additional works at: https://scholarship.kentlaw.iit.edu/ckjip

Part of the Intellectual Property Law Commons

Recommended Citation Recommended Citation Mari Minn PhD, LLM, Assessment of Disclosure In European Prodrug Patent Claims, 18 Chi. -Kent J. Intell. Prop. 429 (2019). Available at: https://scholarship.kentlaw.iit.edu/ckjip/vol18/iss3/6

This Article is brought to you for free and open access by Scholarly Commons @ IIT Chicago-Kent College of Law. It has been accepted for inclusion in Chicago-Kent Journal of Intellectual Property by an authorized editor of Scholarly Commons @ IIT Chicago-Kent College of Law. For more information, please contact [email protected], [email protected].

https://scholarship.kentlaw.iit.edu/ckjip

https://scholarship.kentlaw.iit.edu/ckjip/vol18

https://scholarship.kentlaw.iit.edu/ckjip/vol18/iss3

https://scholarship.kentlaw.iit.edu/ckjip/vol18/iss3/6

https://scholarship.kentlaw.iit.edu/ckjip?utm_source=scholarship.kentlaw.iit.edu%2Fckjip%2Fvol18%2Fiss3%2F6&utm_medium=PDF&utm_campaign=PDFCoverPages

http://network.bepress.com/hgg/discipline/896?utm_source=scholarship.kentlaw.iit.edu%2Fckjip%2Fvol18%2Fiss3%2F6&utm_medium=PDF&utm_campaign=PDFCoverPages

https://scholarship.kentlaw.iit.edu/ckjip/vol18/iss3/6?utm_source=scholarship.kentlaw.iit.edu%2Fckjip%2Fvol18%2Fiss3%2F6&utm_medium=PDF&utm_campaign=PDFCoverPages

mailto:[email protected],%[email protected]

ASSESSMENT OF DISCLOSURE (DO NOT DELETE) 5/20/2019 9:08 PM

429

ASSESSMENT OF DISCLOSURE IN EUROPEAN PRODRUG PATENT CLAIMS

MARI MINN PHD, LLM

ABSTRACT

The article discusses the concept of disclosure in European patent

applications involving prodrugs and active metabolites thereof. The article

begins with an introduction to the scientific aspects of prodrug design to

understand their meaning and difference from common drugs. It is followed

by legal analysis discussing the notion of “disclosure” as an element of

assessing novelty and inventive step. The article argues that the “disclosure”

should be broken off into scientific disclosure affecting novelty criteria and

disclosure as an element of enablement to judge the inventive step. The

arguments of the article is based on the ruling of the United Kingdom (“UK”)

landmark case Merrell Dow Pharmaceuticals v. Norton Limited and Penn

Pharmaceuticals that has dealt with the assessment of novelty criteria by

separating scientific disclosure from disclosure through use. As analyzed in

the article, novelty assessment based on the disclosure doctrine may destroy

the novelty criteria because of scientific “gaps” that may exist in the parent

drug leading to potential infringement by the second-generation claim. The

article also discusses the applicability of the inventive step requirement by

analyzing relevant case law concluding that differently from the novelty

criteria, the later should be applied differently considering explicitly

available information about prior art or in other words, enablement of

disclosure. Therefore, the notion and extent of the disclosure have a versatile

impact on the assessment of the patentability criteria depending on whether

it targets the novelty or the inventive step requirement.

I. THE SCIENCE BEHIND PRODRUGS

Many of the most common medicines are not effective in treating a

large number of patients because of the genetic makeup that is responsible

for determining how a specific drug reacts in a human body. The common

ASSESSMENT OF DISCLOSURE(DO NOT DELETE) 5/20/2019 9:08 PM

430 CHICAGO-KENT JOURNAL OF INTELLECTUAL PROPERTY Vol 18:3

drug research involving a vast quantity of drug molecules cannot provide

targeted solutions that can overcome physiochemical, biological or other

barriers in drug efficiency and/or toxicity. Because of the genetic makeup,

some people metabolize drugs slowly leading to toxic accumulation of the

drug or some people metabolize drugs too quickly which may result in

inefficiency of the drug action in the human body. When a new chemical

entity shows barriers or limitations about its utility, it cannot be developed

further into a therapeutic agent. 1 During the research phase, the most

common problem related to the development of new drugs concerns

solubility problems. Even with the use of current computational “filters” to

minimize this problem, 2 compounds that are active in vitro may lack

adequate pharmacokinetic properties and/or may be difficult to formulate.3

Striving to improve the properties of a given drug and overcome the negative

side effects of an existing drug, prodrugs have become valuable tools for

modern drug development. A prodrug is a pharmacologically inactive

substance4 that must go through a chemical or enzymatic transformation to

become effective inside the body. Thus, the therapeutic rationale behind

prodrugs is to enhance the properties of the parent drug once metabolized in

the body.

According to Huttunen, prodrug strategy has been used to increase the

selectivity of drugs for their intended target. 5 These types of drugs are

striving to offer safer and better-targeted treatment options in modern

medicine. Metabolites6 that are closely related to prodrugs are eventually

formed as a result of a natural biochemical process of degrading and

eliminating compounds. Therefore, to differentiate between prodrugs and

metabolites, it can be said that if the pharmacological effect of a medication

is due to the transformation of a drug into a metabolite, the medication may

1. See generally Valentino J. Stella, Prodrugs: Some Thoughts and Current Issues, 99 J. PHARM. SCI. 4755 (2010).

2. Jarkko Rautio et al., Prodrugs: Design and Clinical Applications, 7 NAT. REV. DRUG DISCOV. 255, 255 (2008).

3. A study conducted with the top 200 oral drug products in Japan, Great Britain, United States, and Spain revealed that approximately 37 percent of drugs had solubilities of less than 0.1 mg/mL See Toshihide Takagi et al., A Provisional Biopharmaceutical lassification of the Top 200 Oral Drug Products in the United States, Great Britain, Spain, and Japan, 3 MOL. PHARM. 631, 635 (2006).

4. The prodrug itself is often biologically inactive but may also possess biological activity—serving as a drug itself.

5. Kristiina M. Huttunen et al., Prodrugs – from Serendipity to Rational Design, 63 PHARMACOLOGICAL REVIEWS, 750, 751 (2011).

6. Edward D. Harris, Biochemical Facts behind the Definition and Properties of Metabolites, https://www.fda.gov/ohrms/dockets/ac/03/briefing/3942b1_08_Harris%20Paper.pdf (last visited Mar. 18, 2019).


2019 ASSESSMENT OF DISCLOSURE IN EUROPEAN PRODRUG 431

be called “a drug” and an “active metabolite”.7 If, on the other hand, the said

effect is due to the release of the drug from a larger chemical entity, then the

medication is called “drug” and “prodrug.”

Prodrugs can masked forms of active drugs that are designed to be

activated after an enzymatic or chemical reaction once they are into the

body.8 Considering that during the R&D process of the parent drug it is not

always possible to foresee all its properties, prodrugs as second-generation

products seek to modify some of the shortcomings of the parent drug

pertaining to absorption, distribution or metabolism. The active metabolite

that is eventually responsible for the drug’s in vivo pharmacological effect

differs structurally from the existing prodrug that is administered to the

patient. 9 A small structural modification, however, may result in major

differences in biological activity.10 Thus, second generation products can not

only serve as a more efficient treatment option but also provide a high return

on investment for a pharmaceutical company. The development of medicine

using an active ingredient, the safety, and efficacy of which have already

been established, is normally less time consuming, less expensive, and less

risky than using a compound about which little is known.11

From the intellectual property law perspective, it is important to

consider that prodrugs are inactive derivatives of drug molecules that were

already contained in the parent drug that is developed to overcome

therapeutic barriers in drug delivery. It means that in most cases prodrugs

are simple chemical derivatives that are only one or two chemical or

enzymatic steps away from the active parent drug as it incorporates an active

molecular entity within another molecular structure. To illustrate this,

according to a study, 49 percent of all prodrugs are targeted at the formation

of esters, which means that they are structurally like the parent drug.12 Some

of the recently approved prodrugs include a very controversial Sofosbuvir

that is challenged by the European Patent Office (“EPO”).

7. HYEWON AHN, SECOND GENERATION PATENTS IN PHARMACEUTICAL INNOVATION, 19 MIPLC

STUDIES 47-49 (2014).

8. See generally, Peter Ettmayer et al., Lessons Learned From Marketed and Investigational Prodrugs, 47 J. MED. CHEM. 2393, 2394 (2004); See generally Valentino J. Stella, Prodrugs: Some thoughts and current issues, 99 J. PHARM. SCI., 4755, (2010).

9. See generally Ralph Minderop et al., Prodrugs and Metabolites – In the Twilight Zone of Patentability?, 2 IP IN THE LIFE SCIENCES INDUSTRIES 9, (2013).

10. Case T 0939/92, Triazoles (1995).

11. Nat’l Inst. for Health Care Mgmt., Changing Patterns of Pharmaceutical Innovation (2002), http://nihcm.org/pdf/innovations.pdf.

12. Jarkko Rautio et al., Prodrugs: Design and Clinical Applications, 7 NATURE REVIEWS 255, 256 (2008).

http://nihcm.org/pdf/innovations.pdf



From a legal point of view, prodrugs may offer a valuable opportunity

to extend the life cycle of the parent drug. It is estimated that prodrugs

account for 5-10 percent of the overall global drug market.13 Most patents

targeting prodrugs are related to oncological research although the range of

truly innovative drugs is, according to the same study, not more than 5-10

percent, which suggests that many of these patents are small improvements

or adjustments of currently existing drugs.

Considering that prodrugs are mainly applied for as secondary patents,

they can add 6.3 additional years to the product life cycle.14 According to

Kapczynski, depending on the category of independent secondary patents,

formulation patents when applied as secondary independent claims add

approximately 6.5 years of patent life, secondary independent claims for

salts, polymorphs, esters, etc., add 6.3 years and independently claimed a

method of use claims add 7.4 years. 15 According to the European

Pharmaceutical Sector Inquiry executed by the European Commission,

applications on second generation patents for bestselling medicines is a

common strategy to evergreen product lifecycle. The number of second

generation patents rises significantly at the end of basic patents. 16 The

Inquiry found that in 40 percent of cases first-generation patents are followed

by second-generation patents and the average time before the launching of

the second-generation patent was estimated to take place 1.5 years before the

expiry of the basic patent. 17 Kapczynski has observed that independent

secondary patents are not obtained randomly but rather the propensity to

obtain secondary patents increases after successful sales suggesting they

reflect deliberate attempts by branded firms to lengthen their monopoly for

more lucrative drugs.18 The EC Pharmaceutical Inquiry Report revealed a

primary to a secondary patent ratio of 1:7 meaning that the number of

secondary patents is much higher in comparison to initial patents obtained in

13. Jarkko Rautio et al., Prodrugs – Recent Approvals and a Glimpse of the Pipeline, 109 EUR. J. PHARMACEUTICAL SCI. 109, 146–61 (2017).

14. Amy Kapczynski et al., Polymorphs and Prodrugs and Salts (Oh My!): An Empirical Analysis of “‘Secondary” Pharmaceutical Patents, 7 PLOS ONE 49470(2012), https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049470.

15. Id.

16. EUROPEAN COMM’N, PHARMACEUTICAL SECTOR INQUIRY REPORT (2009), http://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/staff_working_paper_part1.pdf.

17. Id.

18. Amy Kapczynski et al., Polymorphs and Prodrugs and Salts (Oh My!): An Empirical Analysis of “‘Secondary” Pharmaceutical Patents, 7 PLOS ONE 49470 (2012), https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049470.

.



the beginning of drug lifecycle. 19 The interesting aspect of second-

generation patents is that most studies analyze and estimate the effects of

patenting strategies based on calculations related to the filing date of first-

generation patents20 thus, ignoring the potential effects of second-generation

filings to the patent portfolio lifetime. If secondary patents are frequently

obtained later in the invention cycle then chemical compound patents, this

will underestimate patent life, perhaps substantially.21

Considering that a prodrug is structurally similar to its parent drug, two

questions arise regarding patentability standards of these drugs. The first

question that arises is the extent of disclosure or free use after the expiry of

the parent drug in case a prodrug is claimed later during the life cycle

process. The second question, connected to the first, is the validity of the

prodrug patent in the light of fulfillment of the novelty and inventive step

requirements. This article provides insight into these problems in the

following sections and discusses the normative uncertainties by analyzing

the most relevant case law.

II. THE IMPACT OF DISCLOSURE IN FIRST-GENERATION CLAIMS TO

PRODRUG PATENT APPLICATIONS

Based on the data retrieved from the European Patent Register, it seems

that most patents for prodrugs are claimed as second-generation patents.

There can be several reasons that could explain it. It is possible that, at the

time of filing the first-generation claim, potential shortcomings of the parent

drug were not known which later caused the filing of the second-generation

claim. It is also possible that the shortcomings in the first-generation drug

were actually known already during the first filing, but the second-generation

patent was later used as part of product life cycle management.

It is a fundamental principle of patent practices that after the expiry of

the basic patent the subject matter falls in the public domain meaning that it

becomes accessible to anyone without having to worry about the

infringement. When the subject matter falls in public domain, no further

patent should be granted to the same subject matter; otherwise it would lead

to double patenting. If anyone attempted to craft a patent application

covering the earlier subject matter, under the assumption that the earlier


20. See generally Henry G. Grabowski & John M. Vernon, Effective Patent Life in Pharmaceuticals, 19 INT’L. J. TECH. MGMT. 98 (2000).

21. See generally C. Scott Hemphill & Bhaven N. Sampat, When Do Generics Challenge Drug Patents?, 8 J. EMPIRICAL LEGAL STUD. 613 (2011).



disclosure was complete and enabling enough, it would destroy the novelty

and/or the inventive step requirement. However, considering that prodrug

applications are line extensions of the parent drug, there are a few aspects to

consider.

For a new claim to be patent eligible, a complete and enabling

disclosure is required which is then assessed from the practical point of view.

This means that the disclosure of the claim should be complete enough to

enable a person skilled in the art to perform the invention without undue

burden. Article 84 of the European Patent Convention (“EPC”) states the

following: “The claims shall define the matter for which protection is sought.

They shall be clear and concise and be supported by the description.”22 In

its case law, the EPO has clarified that Article 84 of the EPC requires that

the claims define the subject matter for which patent protection is sought. It

signifies that the disclosure should specify all the essential features needed

to define the invention and that the meaning of these features should be clear

for the person skilled in the art from the wording of the claim.23 Based on the

EPO Board’s interpretation in case T 409/91, the underlying purpose of

Article 83, directed to the disclosure of the invention, is the same as is stated

in Article 84 of the EPC, Namely, to secure the grant of the proper breadth

of patent exclusivity that can be justified by the technical contribution to the

art. 24 The well-established jurisprudence of the EPO in respect to the

interpretation of Article 84 of the EPC, requires that to be patentable, an

independent claim must recite all the essential features which are necessary

for clearly and completely defining a particular invention.25 Therefore, the

claim should define the subject matter by reference to all its essential

technical features. 26 Although the disclosure must contain sufficient

information for the skilled person to perform the invention, there is no

requirement that the inventor should have full scientific understanding

behind the invention. In many situations, it is not possible to add the full

disclosure in the patent application, especially in the case of biotechnological

patents and pharmaceutical patents, as it is not possible to delimit the

invention. From the legal point, the reason why it is relevant to differentiate

between the scientific disclosure and practical (enabling) disclosure is that it

22. See Convention on the Grant of European Patents art. 84, Oct. 5, 1973, 1065 U.N.T.S. 199 [hereinafter European Patent Convention].

23. Case G 0001/04, Diagnostic Methods, OJ EPO 2006, ¶ 6.2.4.

24. Case T 0409/91, Fuel Oils, OJ EPO 1994, 3.5. 25. Case G 0001/04, Diagnostic Methods, OJ EPO 2006, ¶ 6.2.4. 26. Case G 0001/04, Diagnostic Methods, OJ EPO 2006, ¶ 6.2..



defines the extent of the subject matter for which protection is sought and

how it reflects the evaluation of novelty and the inventive step requirements.

It is especially relevant for patents involving prodrugs as a small piece of

scientific information in the disclosure to determine the perspective for

patentability.

According to Article 83 of the EPC, the claim must also contain

sufficient technical disclosure of the solution to the problem. 27 EPO

Guidelines for Examination clarify that a detailed description of at least one

way of carrying out the invention must be given. Therefore, the description

should disclose any essential feature for carrying out the invention by the

person skilled. When the first-generation patent is claimed for the parent

drug, the disclosure should include a number of examples, alternative

embodiments or variations of the subject matter extending over the area

protected by the claim.28

In its case T-0409/91 the EPO Boards of Appeal has held that “The

essential features of the invention, which must be used for defining the

matter for which protection is sought, in accordance with Art. 84 EPC in

combination with Rule 29(1) and (3), are all those technical features which

are necessary to define an invention which is patentable under the EPC,

including any feature which is necessary to define matter which also meets

the requirement of sufficient disclosure pursuant to Article 83.”29

Defining the essential features in the first-generation patent has an

impact on the assessment of novelty in the second-generation patent

application. The scientific disclosure is in direct conflict with the novelty

criteria but according to Art. 54 of the EPC, novelty is judged based on the

information made available at the time of the application. The novelty is thus

judged by the (scientific) knowledge available. The inventive step

requirement, on the other hand, refers to the enabling aspect of the invention

to be carried out by the person skilled in the art. or these reasons, the extent

of disclosure should be analyzed from two different angles, the scientific

disclosure, which is connected to the novelty, and the enabling aspect of the

disclosure, which is connected to the inventive step.

27. See European Patent Convention, supra note 22, art. 83.

28. European Patent Office, Guidelines for Examination, pt. F, ch. III, § 1 (2018),

https://www.epo.org/law-practice/legal-texts/html/guidelines/e/f_iii_1.htm.

29. Case T 198/84, Hoechst ex parte, OJ EPO (1985). In the EPO Case T 292/85 it was stated that

in certain cases a description of one way of performing the claimed invention might be sufficient to

support broad claims with functionally defined features. For example, where the disclosure of a new technique constitutes the essence of the invention and the description of one way of carrying out the

invention enables the person skilled in the art to obtain the same effect of the invention in a broad area

by use of suitable variants of the component features. See Case T 0292/85, Genentech, OJ EPO (1988).



In the case of prodrugs, although being structurally similar to the parent

drug, the main challenge does not arise from the scientific disclosure because

these types of inactive derivatives of original drugs usually contain improved

scientific knowledge. The inability to guarantee a patent for prodrugs stems

rather from the inability to come to terms with the practical aspect of the

disclosure because it raises questions whether a person skilled in the art was

expected to reach to a specific result already during the assessment of the

first-generation claim or not. Differently from prodrugs, the active

metabolites that are the molecules (end products) of a drug (or prodrug) are

generally considered as being already included in the first-generation claim

in Europe from both the scientific, as well as practical, point of view their

“behavior” during metabolism is a natural consequence, therefore they are

excluded from patentability. As a consequence, they do not fulfill even the

novelty requirement.

Still, under some circumstances, the scope of the patent is not limited

to the version that the inventor invented, but could cover the subsequently

modified versions if each falls within the scope.30 It can be deduced that the

inventor is not expected to include a “complete” scientific disclosure in the

patent application, but should provide sufficient information to the examiner

to carry out the invention. For some types of inventions, it can mean that the

disclosure, although sufficient from the practical point of view, may contain

“gaps” from the scientific aspect regarding any of its specific elements.

These elements, on the other hand, can themselves be patentable subject

matter, or may already be encompassed in the disclosure without being

directly referred. For example, prodrugs and especially metabolites thereof

can be viewed as anticipated inventions although they may not have been

previously disclosed in the parent claim. At the same time, prodrugs can be

viewed as a separate subject matter eligible for a new patent. The polemics

here is whether these second-generation prodrug claims should

automatically be refused to avoid a situation where the subject matter of the

first claim is indirectly encompassed in the second-generation claim or find

the prodrug patent valid which could mean that the first-generation invention

is delayed before entering the public domain. The extent of disclosure and

its effects on the novelty and inventive step requirements will be dealt with

in the following sections of this article.

30. Changing Patterns of Pharmaceutical Innovation, supra note 11, at 19.



III. ASSESSMENT OF NOVELTY – THE MERRELL DOW CASE

Prodrugs are chemically modified versions of the pharmacologically

active agent that must transform in vivo to release the active drug. 31

Considering that claims involving prodrugs usually refer to minor

modifications of the structure or the chemical makeup of a molecule 32

meaning that they are only a few steps away from the parent drug, the main

challenge for patenting prodrugs as product related second-generation claims

comes from potential structural similarities to the parent drug of the first-

generation claim. In other words, potential challenges arise from destroying

the novelty and/or inventive step requirements of Articles 54 and 56 of the

EPC. Article 54 requires that “for the invention to be considered novel, it

should not form part of the state of the art.”33 If the concept of an invention

is completely disclosed within a single piece of prior art, it lacks novelty,

regardless of whether it was independently developed from the earlier

invention.34 Thus, the novelty connects to the availability of already existing

information on prior art and the anticipation thereof. In case the invention is

already claimed in an earlier (first generation) invention, the prior disclosure

enables the entire claimed invention in addition to disclosing each and every

element of the invention. 35 According to John F. Duffy, 36 whether the

disclosure forms part of the state of the art depends whether there is a natural

result, meaning that it should be decided whether the later invention is the

natural result flowing explicitly from the earlier disclosure. What has to be

established in the examination as to novelty is whether the state of the art is

such as to make the subject matter of the invention available to the skilled

person in a technical teaching.37

In the case of prodrugs and active metabolites, the question that arises

is how to judge the extent of the scientific disclosure because this type of

second-generation inventions may already have been disclosed in the first

application without being disclosed. In other words, the question is how to

31. Id. at 2.

32. Case T 198/84, Hoechst ex parte, OJ EPO (1985) at 2–3. 33. See European Patent Convention, supra note 22, art. 54.

34. Stephen M. Mauer & Suzanne Scotchmer, The Independent-Invention Défense in Intellectual

Property, 69 ECONOMICA 535–47 (2002). 35. Synthon BV v. SmithKline Beecham plc [2005] H.L. 59, at ¶14.

36. See generally John F. Duffy, Rules and Standards on the Forefront of Patentability, 51 WM. &

MARY L. REV. 638, (2009). 37. Case T 198/84, ¶ 6, A generic disclosure does not destroy the novelty of any of the specific

possibilities falling within the disclosure unless it claims a specific generic feature that encompasses the

latter.



define the extent of the disclosure for the assessment of novelty in the case

of prodrugs and metabolites thereof if they fall within a scientific “gap.” This

means that although they are not explicitly disclosed in the first-generation

application, they are nevertheless anticipated even when the inventor had no

knowledge about such an effect.

What has to be established in the examination as to novelty is whether

the state of the art is such as to make the subject matter of the invention

available to the skilled person in a technical teaching.38 However, different

from the evaluation over the inventive step is that compared and analyzed to

the existing technical criteria, novelty is evaluated not on what it adds to the

existing technical teaching, but whether it can be considered a new invention

overall. In other words, it is whether the subject matter of the invention is

available to the person skilled in the art in technical teaching, which thus

should be an absolute novelty, not a natural result of the existing disclosure.39

Differently, from assessing the inventive step, it is not the newly discovered

effect that is evaluated for novelty, but the new disclosure has to form a new

invention per se. For assessing novelty of second-generation claims, it is not

important whether there is a technical effect present over the prior art as this

is evaluated at the stage of analyzing the existence of the inventive step.

However, what is important about the technical teaching in the context of

novelty is that the second-generation patent should not disclose a teaching

that is anticipated by the examiner as a “natural result” of the first-generation

claim.

When the first-generation claim covering the parent drug already

included a possible (future) prodrug derivative, the novelty criteria in the

second-generation claim could not be met. The teaching of the prior art is

not confined to the detailed information given in the examples of how the

invention is carried out40 but relies on the information available in the claims

and the description of the application that becomes the starting point for the

person skilled in the art to carry out the invention and test novelty. For this

reason, according to the established EPO case law,

In the case of one of a number of chemical substances described by its structural formula in a prior publication, that substance’s particular stereospecific configuration (thereof form) - though not explicitly

38. Id. at ¶ 6. 39. The new disclosure should not be a mere embodiment of the prior disclosure but is expected to

form another invention. See Case T 0279/89, In re Texaco Dev. Corp., OJ EPO (1991) ¶ 4.1.

40. Case T 0012/81, In re Bayer AG, OJ EPO (1982).



mentioned - is anticipated if it proves to be the inevitable but undetected result of one of a number of processes adequately described in the prior publication by indication of the starting compound and the process.41

Thus, when deducting this reasoning to prodrugs, if the second-generation

family of the compound partially already covered what was disclosed in the

first-generation disclosure, novelty cannot be approved. But at the same

time, “if the (second-generation) subject matter is a defined compound,

whereas the prior art discloses a family of [a] compound defined only by a

general formula covering the defined compound, but not describing it

explicitly, the invention must be considered novel.”42

Deducing from the EPO case law, the second-generation claim may

nevertheless fall within the scope of the parent claim, even if it was not

explicitly described as the disclosure of the parent claim that could already

anticipate the subject matter of the other claim due to the scientific “gap” or,

in other words, explicit anticipation. Therefore, the success of the second-

generation patent application relies on available knowledge, the extent of

disclosure, and the wording of the patent application concerning what is

claimed.

The validity of prodrug and metabolite patents in Europe has been dealt

with in the landmark case Merrell Dow v. H.N. Norton & Co. Ltd. in the

UK43. The case concerned a metabolite of Terfenadine, which was a line

extension of the original drug patented in the 1970s. Considering that the

second-generation patent involving a metabolite was patented a decade later,

a generic drug company Norton challenged the metabolite patent as a de

facto extension of the original drug based on validity and/or infringement.

The case was under discussion in the U.S., Germany and the UK. In the first

two countries, the main challenge was about patent infringement whereas the

litigation brought up in the UK was the only country challenging the validity

of metabolite claims. Therefore, the questions regarding novelty and

inventive step arose in the context of challenging patent validity. Generally,

41. See supra, Section II. 42. The Board stated the following: “If a mere precisely structurally defined (described by a chemical reaction) class of chemical compounds with only one generically defined substituent does not represent a prior disclosure of all the theoretical compounds encompassed by an arbitrary choice of a substituent definition, it must be clearly valid for a group of chemical substances, the general formula of which has two variable groups. Therefore, in the present case, a class of chemical compounds, defined only by a general structural formula having at least two variable groups does not specifically disclose each of the individual compounds which would result from the combination of all possible variants within such groups.” Case T 0007/86, DRACO v. Napp Labs. Ltd., OJ EPO (1987) ¶ 5.1.

43. Merrell Dow Pharms. Inc v. Norton & Co. Ltd., [1996] 3 RPC 76 , 87 (H.L.).



for a patent in the second-generation application to be held invalid for the

lack of novelty, the prior art should disclose the same invention. In Merrell

Dow, Lord Hoffmann invalidated the patent for having been anticipated by

disclosure.44 The notion and extent of the disclosure were addressed in detail.

Referring to Art. 54 of the EPC, it was found that what constitutes

anticipation is not simply something that was done before.45 To determine

the extent of the disclosure and consequently, judge novelty, it should be

clarified what constitutes prior art in terms of “use” and (scientific) and

“disclosure.” Lord Hoffmann made a distinction between these terms as he

considered that for the prior art to have a destructive impact on the

assessment of novelty through use required that the information should have

been made public through its use which, in this specific case, was not an

issue. Instead, the judge found that the disclosure does not mean everything

made available to the public in a written form or by public statement. The

view was the disclosure by itself can contain information without being made

public through use, meaning that the result of the metabolite action in the

human body was due to the scientific disclosure (which was not, at the time,

known to the inventor) rather than due to the communication to the public

through its use. Thus, the second-generation invention should be anticipated

based on the (scientific) disclosure that enables a person skilled in the art to

convey sufficient information to work the invention.46 This means that the

anticipation by “use” has a different basis than anticipation by (scientific)

“disclosure”.

For purposes of clarifying the difference between these terms, Lord

Hoffmann stated the following referring to the CPC/Flour Concentrate

case47:

if the recipe which inevitably produces the substance is part of the state of the art, so is the substance as made by the recipe. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.48

It seems what the judge had in mind is that when the subsequent

invention was performed based on the disclosure, it would necessarily have

led to the infringement of the initial patent. Thus, the outcomes of performing

44. Merrell Dow Pharms. Inc v. Norton & Co. Ltd., [1996] 3 RPC 76 , 87 (H.L.).

45. Id. at 84.

46. Id. at 34

47. Id.

48. Id. at 90.



the second-generation invention should not be one of the possible options or

result, but it should be based on the information disclosed even when it was

not explicitly described in the patent. It should be anticipated. If it is one of

the possible consequences, one cannot say that performing this invention

would infringe.49 This statement is supported by Union Carbide Corporation

v. Basf AG, Dow Chemical Co. and NV DSM. Here, the EPO Boards of

Appeal concluded that:

“[i]t may be easy, given a knowledge of a later invention, to select from the general teachings of a prior art document certain conditions, and apply them to an example in that document, so as to produce an end result having all the features of the later claim. However, success in so doing does not prove that the result was inevitable. All that it demonstrates is that, given knowledge of the later invention, the earlier teaching is capable of being adapted to give the same result. Such an adaptation cannot be used to attack the novelty of a later patent.”50

In the case of metabolites that make an effect on the molecular level as

the end products after being metabolized, it is expected that when performing

the first-generation invention involving a drug it would necessarily result in

the same effects as the second-generation metabolites do. Therefore, the

result should be expected in the first-generation patent. Also, as discussed in

Merrell Dow, the (scientific) disclosure that sets the basis for the evaluation

of novelty may not be known to the inventor himself51 Nevertheless, it does

not make the following claim valid. What matters is the disclosure must

necessarily result in an infringing invention in the second-generation claim

once performed. This is what sets novelty apart from the practical

enablement or in other words, inventive step requirement. In Merrell Dow,

the ingestion of terfenadine by hay-fever sufferers, which was the subject of

prior disclosure, necessarily entailed the making of the patented acid

metabolite in their livers. 52 It was, therefore, an anticipation of the acid

metabolite, even though no one was aware that it was being made or even

that it existed. A similar view regarding the assessment of novelty in light of

judging the extent of disclosure was seen in Synthon v. SmithKline Beecham

in the UK, which contested a patent for a crystalline form of paroxetine

49. Lord Hoffmann said, “. . . the prior disclosure must be construed as it would have been understood by the skilled person at the date of the disclosure and not in the light of the subsequent patent.”

Id. at 84.

50. Case T 0396/89, Union Carbide Corp. v. BASF Aktiengesellschaft et al., OJ EPO (1991) ¶ 4.4 51. Synthon BV v. SmithKline Beecham plc [2005] H.L. 59, at 23.

52. Id. at 23.



Methosulfate. 53 In Synthon, the judge sought to separate the notion of

disclosure from enablement since disclosure concerns novelty and

enablement concerns the obviousness/inventive step.54

As for assessing the novelty criteria in the light of prior disclosure, the

judge came to a similar conclusion as in Merrell Dow. The judge concluded

that relying on prior art should disclose the subject matter in a manner that,

if performed, it would necessarily result in patent infringement.55 Based on

these judgments, it can be concluded that for the assessment of novelty

concerning prodrugs and/or active metabolites the main doubt concerns the

extent of the scientific disclosure within the first-generation claim. In

evaluating disclosure, it does not matter whether the second-generation

subject matter was explicitly mentioned in the parent claim because, from

the scientific point of view, this type of subject matter is anticipated. The

existence and advantages of the second-generation subject matter are

generally, in this situation, disclosed because carrying out the invention

would inevitably lead to the production of the second-generation product by

the person skilled in the art. Although the concept of the invention is not

completely disclosed in the first claim, if the subject matter of the second-

generation claim would fall within the scientific “gap” disclosed in the parent

drug, the result would inevitably lead to the construction and or effects of the

prodrug/metabolite claim. The Court interpreted the novelty provision to

find that the earlier patent had put information about the Terfenadine

metabolite into the public domain, despite not publicly teaching the ‘missing

element’ in the patent specification.56 The findings and reasoning of the

decision in Merrell Dow are well-suited for justifying the inexistence of

novelty in the following patent application to avoid evergreening attempts as

part of drug life cycle management. Certainly, each case is judged based on

its contents, but the UK judgment has followed the same approach denying

metabolite patents in Europe as did the EPO. However, prodrugs are still

patentable subject matter in Europe as they are in the UK, but the passing of

the novelty test based on the contents of the disclosure depends on the

wording of a claim and the extent of the scientific disclosure. The following

section of the article discusses the understanding of disclosure within the

53. Id. at 23.

54. Id. at 66.

55. Id. at 22. 56. See generally H. Samuel Frost, The Unique Problem of Inventions which are Fully Enabled and

Fully Described but not Fully Understood(Merrell Dow’s Terfenadine Revisited), 15 INTELL. PROP. J.

2,(2007).



notion of enablement as a means of assessing the inventive step in prodrug

and metabolite patent applications in Europe.

IV. DISCLOSURE AS AN ELEMENT OF ENABLEMENT FOR ASSESSING THE

INVENTIVE STEP

It has been an accepted legal principle that the extent of the patent

monopoly should correspond to and be justified by the technical contribution

to the state of art.57 Therefore, the extent to which an invention is sufficiently

disclosed as an element of enablement is highly relevant for the evaluation

of second-generation patent applications. The inventive step requirement is

considered the “final gatekeeper of the patent system.”58 This means that

even if relatively trivial changes to the prior art could survive the novelty

and industrial applicability requirements, the inventive step will function as

the ultimate requirement and filter the patentable from the unpatentable.59

The relevance of the inventive step requirement is to guarantee there is a

technical advancement in the teaching in comparison to the state of the art.

It should not be an extension or incremental development of technology,60

which may pass the novelty check but would add nothing to the level of

technological advancement.

The inventive step can only be assessed when the invention is deemed

novel. In comparison to the novelty, the inventive step seems to have higher

standards of applicability. Art. 56 of the EPC defines the inventive step in

the following manner: “An invention shall be considered as involving an

inventive step if, having regard to the state of the art, it is not obvious to a

person skilled in the art.”61 While both of these definitions deal with the state

of art the novelty criteria is informative. To pass the evaluation, the main

factor considered is the available information of prior art as discussed in the

previous section. Novelty is judged based on the scientific disclosure, which

may mean that this information can fall in the scientific “gap,” which

nevertheless can destroy novelty. The inventive step requirement, on the

other hand, refers to the technical teaching, which means in addition to being

novel to the examiner, the invention should contain a new technical

57. Case T 0409/91, In re Exxon Chem. Patents, Inc., (1993) at 3.3 (Eur. Pat. Bd. of App.). 58. R. P. MERGES & J. F. DUFFY, PATENT LAW AND POLICY: CASES AND MATERIALS 619–20

(LexisNexis, 5th ed. 2011).

59. Id. at 620. 60. Mark F. Grady & Jay L. Alexander, Patent Law and Rent Dissipation, 78 VA. L. REV. 305, 340

(1992).

61. See European Patent Convention, supra note 22, art. 56.



contribution to the state of the art. While the novelty requirement puts the

examiner in a passive state,62 the inventive step requirement has the opposite

effect as it requires the active participation of the person skilled in the art to

perform tests and make the ultimate evaluation. The inventive step requires

that the invention, based on the prior art, is not obvious to the examiner. For

assessing the inventive step, the problem-solution approach is used. This

means that the second-generation claim should provide a technical problem

over the prior art that needs to be “solved” to see whether the solution can

be considered inventive (non-obvious) in comparison to the existing

knowledge. 63 Thus, an unexpected advantage that could not have been

predicted from the prior art is taken as evidence of an inventive step. In this

light, for the fulfillment of the inventive step requirement, the newly claimed

compound/molecule should present a special technical property that is not

previously disclosed. It means that the second-generation claim should offer

a “surprising” technical effect to the existing prior art. In the case of

prodrugs, it can be either a new property or a better activity in comparison

to the existing invention.

In the case of chemical inventions concerning potential structural

similarity, the EPO has taken the view64 that “to deny the patent for the lack

of the inventive step, a skilled person should be expected to find the same or

similar usefulness in comparison to the known compound as means of

overcoming the technical problem.” What makes the difference is the range

of structural differences of the second-generation drug when compared to the

parent compound. If these differences are lacking or very small, they would

have an insignificant bearing on those properties that are essential for solving

the technical problem at issue. Because of structural similarities with the

parent drug, the inventive step for a prodrug often turns on the structural

similarities and differences between the claimed compound and prior art.65

In T 2402/10 the board stated “in the field of drug design any structural

modification of a pharmacologically active compound is, in the absence of

an established correlation between structural features and activity, a priori

62. Id.; Frost, supra note 56, at 19.

63. In assessing the inventive step, the EPO has applied the following three-step test: “1. Determining the ‘closest prior art’; 2. Establishing the ‘objective technical problem’ to be solved; and 3.

Considering whether or not the claimed invention, starting from the closest prior art and the objective

technical problem, would have been obvious to the skilled person.” See Implementing Regulations – to

the Convention on the Grant of European Patents of 5 October 1973.

64. Case T 0358/04, Retroviral protease inhibitors/G.D. SEARLE, OJ EPO (2006) ¶ 4.5.3 .

65. JARKKO RAUTIO, PRODRUGS AND TARGETED DELIVERY: TOWARDS BETTER ADME

PROPERTIES 73 (Wiley 2011).



expected to disturb the pharmacological activity profile of the initial

structure.”66 In the case of prodrugs, the structural similarities in the first-

and second-generation claims can otherwise lead to double patenting if the

inventive step is not approached with caution. Double patenting can be raised

where the subject matter of the granted invention is encompassed by the

claim later put forward.67 However, what makes the difference whether the

inventive step stage is passed successfully or not is whether the second-

generation claim has distinguishing features in comparison to the first-

generation claim. Under this condition, the subject matter of the second-

generation claim and the first-generation claim cannot be considered as “the

same subject matter. Thus, the evaluation of the inventive step has stricter

standards in Europe when compared to the assessment of the novelty criteria.

The inventive step has to occur for the entire selection range, but the novelty

criteria is fulfilled when the claimed subject matter is distinguished from the

prior art in the range of overlap by a new technical element.68

As discussed in the previous section, to destroy novelty, the disclosure

must infringe the invention If the performance of an invention would make

the second-generation subject-matter obvious to the person skilled in the art

but not necessarily infringe the first one, then one can discuss the practical

enablement in judging the inventive step, not novelty.69 Therefore, while

Merrell Dow divided the destruction of novelty into two categories, namely

disclosure by use and scientific disclosure, the inventive step requirement is

connected to the practical enablement of the disclosure. Enablement means

that a person skilled in the art should be able to perform the invention, which

satisfies the requirement of disclosure.70 Thus, the inventive step can be

judged based on what is previously disclosed, meaning that for the

destruction of the inventive step, either the prior disclosure of the invention

or general common knowledge would have enabled a person skilled in the

art to make it.71 The inventive step depends on what is disclosed in the prior

art making it different from novelty, which may be judged, based on Merrell

Dow, also on the “missing” information (the scientific “gap”) in the

disclosure made available.

In Union/Carbide, the EPO Boards of Appeal clarified that:

66. Case T 2402/10, Prostaglandin derivatives / Pfizer, OJ EPO (2012). 67. Case T 0307/03, ARCO/Double patenting, [2007] (Eur. Tech. Bd. of App.).

68. Case T 0012/90, Bayer AG, OJ EPO (1990). 69. Id.; Synthon BV v. SmithKline Beecham plc [2005] H.L. 59, at 49.

70. Id.; Case T 0396/89, Union Carbide Corp. v. BASF Aktiengesellschaft et al., OJ EPO (1991).

71. Asahi Kasei Kogyo KK’s Application [1991] RPC 485 (HL).



It may be easy, given a knowledge of a later invention, to select from the general teachings of a prior art document certain conditions, and apply them to an example in that document, so as to produce an end result having all the features of the later claim. However, success in so doing does not prove that the result was inevitable. All that it demonstrates is that, given knowledge of the later invention, the earlier teaching is capable of being adapted to give the same result. Such an adaptation cannot be used to attack the novelty of a later patent.72

If the disclosure of prior art would make it obvious to the skilled person how

to adapt the invention in a manner that could eventually result in

infringement, one can challenge the inventive step but not novelty because

the infringement would be based on the existing available information of

prior art. Secondly, enablement would not mean an automatic and inevitable

infringement, but it is one of the possibilities that may lead to such

infringement if adaptions are made. In other words, enablement means that

for the destruction of the inventive step, the skilled person is expected to

perform the invention, which satisfies the requirements of disclosure. Based

on Hill v. Evans,73 for the assessment of novelty, no further experiments with

the subject matter are performed as it is judged based on the (scientific)

disclosure. Given Merrell Dow, the argument in Union/Carbide and Hill v.

Evans is different because of the case’s substantial circumstances. Namely,

the intriguing aspect of Merrell Dow was that the second-generation

invention disclosed in the prior art was not the same as claimed in the

invention itself, but if performed by the examiner, it would infringe the

claimed invention. In this case, the debate concerned whether the disclosure

contained in the prior art enabled the examiner to make Terfenadine, not

whether it enabled him to make metabolites. This makes judging novelty

different from the inventive step and the questions that were raised regarding

validity in Merrell Dow concerned novelty, not the inventive step.

72. Id.; Case T 0396/89, Union Carbide Corporation v. BASF Aktiengesellschaft et al., OJ EPO

(1991) ¶ 4.4.

73. In Hill v. Evans in the UK, the House considered what would amount to disclosure of an invention. Lord Westbury LC said “I apprehend the principle is correctly thus expressed: the antecedent

statement must be such that a person of ordinary knowledge of the subject would at once perceive,

understand and be able practically to apply the discovery without the necessity of making further experiments and gaining further information before the invention can be made useful. If something

remains to be ascertained which is necessary for the useful application of the discovery, that affords

sufficient room for another valid patent.” Hill v. Evans, (1862) 31 LJ (NS) 457, 463.



CONCLUDING REMARKS

Although second-generation patents are sometimes seen as lacking true

inventiveness and, therefore, should perhaps not be granted,74 it is not always

the case. The main concern about drug patent has been the issuing of

secondary patents with questionable value, meaning that although a patent

can qualify from the technical point of view for a new patent but it may not

necessarily have any significant therapeutic value from the medical aspect.

It has therefore been questioned whether these types of patents rather reflect

their input and true innovative value. Lemley and Shapiro have pointed out

that among the vast number of patents filed most of them have little value

and such patenting leads to a situation where third parties have no

meaningful opportunity to participate in the patent granting system. 75

Burdon and Sloper state that “[a] key element of any lifecycle management

strategy is to extend patent protection beyond the basic patent term for as

long as possible by filing secondary patents, which are effective at keeping

generics off the market.”76 According to the Pharmaceutical Sector Inquiry,

which studied the tendencies of European pharmaceutical companies to use

sequential patents, the primary-to-secondary patent ratio is 1:7, and

interestingly, the ratio for pending patents is much higher in comparison to

granted patents.77 Another study conducted in the U.S. market suggested that

around half of pharmaceutical products are additionally covered with follow-

on patents.78

Lemley and Shapiro79 argue that “[m]odern technologies incorporate

not one but a number of combinations of patents for different components of

the basic invention.” A study conducted by Stella has suggested that, in many

cases, a look at the structure of the active drug with the additional claim of

prodrugs suggested that prodrugs would serve minimal advantage. 80

According to his estimation, the vast majority of prodrug patents contain

74. Id.; Asahi Kasei Kogyo KK’s Application [1991] RPC 485 (HL). 75. See generally Mark A. Lemley & Carl Shapiro, Probabilistic patents, 19 J. ECON. PERSP. 75 (2005).

76. Michael Burdon & Kristie Sloper, The Art of Using Burden Secondary Patents to Improve

Protection, 3 INT’L J. MED. MARKETING, 226, 266 (2003).


78. See generally Amy Kapczynski et al., Polymorphs and Prodrugs and Salts (Oh My!): An

Empirical Analysis of “‘Secondary” Pharmaceutical Patents, 7 PLOS ONE 49470 (2012).

79. See generally Mark A. Lemley & Carl Shapiro, Patent Holdup and Royalty Stacking, 85 TEX.

L. REV. 1992 (2007).

80. See generally Valentino J. Stella, Prodrugs: Some thoughts and current issues, 99 J. PHARM.

SCI. 4755 (2010).



little true novelty either in the chemical or biological sense meaning that less

than 5-10 percent of the patents represent true creativity.81 Correa has made

a similar conclusion arguing that “[a] claim on a prodrug will generally fail

to meet the inventive step standard unless evidence is provided that it

overcomes pharmaceutical or pharmacokinetically based problems of the

parent drug in a non-evident manner.”82

Although the improved efficacy of prodrugs in overcoming the barriers

in parent drug delivery can be disputed, the standards applicable to these bio-

reversible derivatives of drug molecules consider the technical side of

claimed inventions. A key consideration under patent law is whether the

development of a new prodrug is the outcome of an inventive activity or of

routine research and experimentation. The first question that was addressed

in these article was the extent of disclosure in second-generation patent

applications concerning prodrugs. The second question, which is closely

connected to the first one, is the validity of the prodrug patents in the light

of fulfillment of novelty and inventive step requirements. To analyze these

issues, this article provided an overview about the scientific notion of

prodrugs and active metabolites explaining that because of structural

similarities with the parent drug, prodrugs and active metabolites face

challenges in overcoming the patentability criteria pertaining in the

European Patent Convention. This article further analyzed the understanding

of the term “disclosure” in European patent applications arguing that the

scientific disclosure should be separated from the practical disclosure as they

are targeted to judging different criteria of patentability. The extent of

disclosure has a direct impact on the assessment of novelty and the inventive

step requirements in European patent application. As analyzed in Merrell

Dow the scientific disclosure relates to the novelty criteria. Deduced from

the analysis in Merrell Dow, it was concluded that although novelty is

generally assessed based on the information made available to the public, in

cases involving subject matter targeting prodrugs and metabolites, it is

possible that the scientific disclosure that sets the basis for the assessment of

novelty, falls within the scientific “gap” meaning that it may not even be

communicated to the public to be considered as prior art. Thus, although

novelty contains the element of anticipation, one should distinguish between

anticipation by “use” and by (scientific) “disclosure.” When this discussion

is applied to the assessment of novelty for prodrugs and metabolite patents,

81. Id. at 4755. 82. Carlos M. Correa, Guidelines for Pharmaceutical Patent Applications: Examining Pharmaceutical Patents from Public Health Perspective, UNDP, at 10 (2015), https://www.undp.org/content/dam/undp/library/HIV-AIDS/UNDP_patents_final_web_2.pdf.

https://www.undp.org/content/dam/undp/library/HIV-AIDS/UNDP_patents_final_web_2.pdf



the disclosure, even if not directly stated in the application of the parent drug,

would inevitably infringe that patent if the second invention was performed.

Thus, the prodrug/metabolite should (from the scientific perspective) be

expected to contain the parent drug already.

The article also dealt with the legal analysis concerning the assessment

of the inventive step arguing that the disclosure should be based strictly on

the information made available the prior art. Differently, from the scientific

disclosure that is a passive notion, the disclosure involving enablement

requires active performance from the examiner to conduct tests with the

subject matter. To destroy the inventive step requirement, enablement should

be based on the information available in the prior art and the examiner should

be capable of performing the invention as disclosed.

chicago-kent journal of intellectual property

Documents